EP0655060A1 - Pharmaceutically active diketopiperazines - Google Patents
Pharmaceutically active diketopiperazinesInfo
- Publication number
- EP0655060A1 EP0655060A1 EP93918032A EP93918032A EP0655060A1 EP 0655060 A1 EP0655060 A1 EP 0655060A1 EP 93918032 A EP93918032 A EP 93918032A EP 93918032 A EP93918032 A EP 93918032A EP 0655060 A1 EP0655060 A1 EP 0655060A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- piperazinedione
- benzylidene
- compound
- methoxybenzylidene
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the present invention provides the use of a diketopiperazine of formula (A) :
- each of R., to R 10 is independently selected from hydrogen, C,-C 6 alkyl unsubstituted or substituted by one or more halogen atoms, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH 2 OH, -CH 2 COOH, -C0 2 R 11 , -NHCOR 11 , -NHS0 2 R 13 , -S0 2 R 13 , -C0N(R 11 R 12 ) , -SOR 13 , -S0 2 N(R 11 R 12 ) , -N(R 11 R 12 ), -0 (CH 2 ) n N (R 11 R 12 ) , -0(CH 2 ) n C0 2 R 11 , -0C0R 11 , -CH 2 NHC0R 11 , -CH
- one of rings a and b is unsubstituted or is mono-substituted whilst the other ring is unsubstituted or is substituted at one or more of positions 2 to 6.
- the ring which is mono-substituted may carry the substituent at any one of positions 2 to 6, for instance position 3 or 4, especially position 4.
- one of R 6 to R 10 is other than hydrogen, preferably R 7 or R g , especially R g .
- one of R, to j is other than hydrogen, preferably R 2 or R 3 , especially R 3 .
- the substituent R, to R j , or R 6 to R 10 respectively is preferably selected from a halogen, for instance fluorine; an alkoxy group, for instance OMe; and an acetamido group -NHAc in which Ac denotes acetyl.
- the other ring may bear any desired substitution pattern. For instance, the other ring may be unsubstituted or may be mono-, di- or tri-substituted at any of positions 2 to 6.
- the said other ring may, for instance, be mono- substituted at any of positions 2 to 6. It may also be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- disubstituted, or 2,3,4-, 2,3,5-, 2,3,6- or 3,4,5-trisubstituted.
- R 1 to R j when the said other ring is a and is mono-substituted, four of R 1 to R j are hydrogen and one is other than hydrogen.
- three - A - of R- to R j are hydrogen and two are other than hydrogen.
- R, and R 2 , or R 1 and R 3 , or R 1 and R , or R, and R j , or R 2 and R 3 , or R 2 and R 4 are other than hydrogen whilst, in each case, the other three of R, to R j are hydrogen.
- R 1 to R j are hydrogen and three are other than hydrogen.
- R,, R 2 and R 3 , or R,, R 2 and R 4 , or R ⁇ R 2 and R j , or R 2 , R 3 and R 4 are other than hydrogen whilst, in each case, the other two of R, to R j are hydrogen.
- R 6 to R 10 When the said ring is b and is mono-substituted, four of R 6 to R 10 are hydrogen and one is other than hydrogen. When the said other ring is b and is di-substituted, three of R 6 to R 10 are hydrogen and two are other than hydrogen.
- R 6 and R 7 , or R 6 and R g , or R 6 and R,, or R 6 and R 10 , or R 7 and R g , or R 7 and R, are other than hydrogen whilst, in each case, the other three of R 6 to R 10 are hydrogen.
- the said other ring When the said other ring is b and is trisubstituted, two of R 6 to R 10 are hydrogen and three are other than hydrogen.
- R 6 , R 7 and R g , or R 6 , R 7 and R ⁇ ,, or R 6 , R 7 and R 10 , or R 7 , R g and R-, are other than hydrogen whilst, in each case, the other two of R 6 to R 10 are hydrogen.
- any two adjacent substituents in the said other ring may, together with the carbon atoms to which they are attached, complete a second benzene ring which is optionally substituted, thus forming an optionally substituted naphthyl group with the said other ring.
- R 1 and R 2 may form together with carbon atoms 2 and 3, or 3 and 4 respectively, an optionally substituted benzene ring which, in turn, forms with ring a a naphthyl group which i ⁇ unsubstituted or substituted by one or more groups specified above for R 1 to R 10 .
- R 6 and R 7 or R 7 and R g may form, together with carbon atoms 2 and 3 or 3 and 4 respectively, an optionally substituted benzene ring which, in turn, forms with ring b a naphthyl group which is unsubstituted or substituted by one or more groups specified above for R, to R 10 .
- the naphthyl group in either case is unsubstituted or is monosubstituted at position 1,2,3 or 4 of the naphthalene ring structure, especially position 4.
- each of R 6 to R 10 is hydrogen.
- one of R 6 to R 10 is selected from alkoxy, NHCOR 1 and halogen and the other four of R 6 to R 10 are H.
- Alkoxy may be, for instance, OMe or 0Bu n .
- NHCOR 11 is typically - NHAc.
- Halogen is typically F or Cl.
- R g is alkoxy, especially OMe or 0Bu n ; NHCOR 11 , especially -NHAc; or halogen, especially F or Cl; and each of R 6 , R 7 , , and R 10 is H.
- R, to R j are all hydrogen, or one or two of R 1 to R j are other than hydrogen whilst the others are hydrogen.
- R 1f R 2 and R 3 is other than hydrogen.
- R 1 and R 3 , or R 2 and R 3 are other than hydrogen.
- Preferred values for the one or two of R 1 to R j which is or are other than hydrogen include alkoxy such as OMe or 0Bu n , halogen such as Cl or F, hydroxy, -N(R 11 R 12 ) , -C0 2 R 11 , -CH 2 SCOR 13 , -CH 2 SR 11 , -NHCOR 11 , -0(CH 2 ) n N(R R 12 ) , -O(CH 2 ) n C0 2 R 11 , -CH 2 NHC0(CH 2 ) n C0 2 R 1 , -NHC0CH 2 0R 11 , -NHCO(CH 2 ) n OCOR 11 , -CH 2 NHCOOR 13 and CF 3 . It is also preferred for R, and R 2 , R j and R 3 , R 3 and R 4 or R 4 and R j to form, together with the carbon atoms to which they are attached, a benzene
- R, and R 2 are independently H, nitro or halogen
- R 3 is H, hydroxy, -0(CH 2 ) n N(R 11 R 12 ) , -OCOR 11 , -0(CH 2 ) n C0 2 R 11 , -CH 2 NHCO(CH 2 ) n C0 2 R 11 , C,-C 6 alkoxy, -NHCO(CH 2 ) n OCOR 11 , -N(R 11 R 12 ), -CH-,NHC0 2 R 13 , -CH 2 SR 11 or -NHCOR 11 ;
- R 4 is H, halogen, C 1 -C 6 alkoxy, -CH 2 SCOR 11 , -CH 2 SR 11 or -C0 2 R 11 ; and
- R j is H, nitro or halogen; or R 2 and R 3 , R 3 and R 4 or R 4 and R j form, together with the carbon atoms to which they are attached, an
- R g is OMe, each of R 6 , R 7 , R, and R 10 is H; R 1 is H, nitro or halogen such as Cl; R 2 is H; R 3 is H, hydroxy, -OCOR 11 such as OAc, -NHCO(CH 2 ) n OCOR 11 such as -NHCOCH 2 OAc or -NHCOCH 2 OR 11 such as -NHCOCH 2 OH; R 4 is H and j is H or halogen such as F or Cl; or R 2 and R 3 form a benzene ring together with the carbon atoms to which they are attached.
- R 1 is H, nitro or halogen such as Cl
- R 2 is H
- R 3 is H, hydroxy, -OCOR 11 such as OAc, -NHCO(CH 2 ) n OCOR 11 such as -NHCOCH 2 OAc or -NHCOCH 2 OR 11 such as -NHCOCH 2 OH
- R 4 is H and
- each of R,, R 6 , R 7 , R g , R-, and R 10 is H;
- R 2 is H and
- R 3 is -CH 2 SR 11 such as -CH 2 SMe, -CH 2 SCOR 11 such as -CH 2 SAc, -NHCO(CH 2 ) n C0 2 R 11 such as -NHCO(CH 2 ) 3 C ⁇ 2 Me, -0(CH 2 ) n C0 2 R 11 such as -0(CH 2 ) 4 C0 2 H, -0(CH 2 )N(R 11 R 12 ) such as -0(CH 2 ) 3 -NMe 2 , or -N(R 11 R 12 ) such as -NMe 2 or R 2 is -CH 2 SCOR 13 such as -CH 2 SAc or -CH 2 SR 11 such as -CH 2 SH and R 3 is H; and R 4 and R j are both H or both form, together with the carbon atoms to which they are attached
- General formula A embraces diketopiperazines which are novel. Accordingly, the present invention provides a diketopiperazine of formula (A) as defined above, or a pharmaceutically acceptable salt or ester thereof; with the exception of compounds wherein:
- R, to R j are defined above and are optionally protected, in the presence of a base in an organic solvent; or (ii) condensing a compound of formula (I'):
- R 1 to R j are as defined above and are optionally protected, with a compound of formula (III) :
- a compound of formula A produced directly by the condensation reaction between (I) and (II) or (I') and (III) may be modified, if desired, by converting one or more of groups R, to R 10 into different groups R, to R 10 .
- These optional conversions may be carried out by methods known in themselves.
- a compound of formula A in which one or more of R 1 to R 10 is an ester group may be converted to a compound of formula A wherein the corresponding substituent is a free -COOH group, by acid or alkaline hydrolysis at a suitable temperature, for example from ambient temperature to 100*C.
- a compound of formula A in which one or more of R 1 to R 10 is a -C0 2 H group may be converted into a compound of formula A wherein the corresponding substituent is esterified by esterification, for example by treating the carboxylic acid with a suitable C 1 -C 6 alkyl alcohol in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.
- a compound of formula A in which one or more of R, to R 10 is a free -C0 2 H group may be converted into a compound of formula A in which the corresponding substituent is a group -CON(R 11 R 12 ) , wherein R 11 and R 12 are as defined above, for example by treatment with ammonia or an amine in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.
- a compound of formula A in which one or more of R 1 to R 10 is a free -C0 2 H group may be converted into a compound of formula A wherein the corresponding substituent is a -CH 2 OH group by reduction, for example using borane in a suitable solvent such as tetrahydrofuran.
- a compound of formula A in which one or more of R 1 to R 10 is a nitro group may be converted into a compound of formula A in which the corresponding substituent is an amino group by reduction under standard conditions, for example by catalytic hydrogenation.
- Protecting groups for R, to R 10 in any of the compounds of formulae (I), (I ' ) , (II) and (III) are optionally introduced prior to step (i) or step (ii) when any of groups R, to R 10 are groups which are sensitive to the condensation reaction conditions or incompatible with the condensation reaction, for example a -COOH, -CH 2 OH or amino group.
- the protecting groups are then removed at the end of the process. Any conventional protecting group suitable for the group R, to R 10 in question may be employed, and may be introduced and subsequently removed by well-known standard methods.
- the compounds of formula (I) may be prepared by a process comprising reacting l,4-diacetyl-2,5- piperazinedione with a compound of formula (III) as defined above, in the presence of a base in an organic solvent.
- the compounds of formula (I') may be prepared by a process which comprises reacting l,4-diacetyl-2,5- piperazinedione with a compound of formula (II) as defined above, in the presence of a base in an organic solvent.
- the resulting compound of formula (I) or (I') can be separated from other reaction products by chromatography.
- the reaction of l,4-diacetyl-2,5-piperazinedione with the compound of formula (III) or (II) is suitably performed under the same conditions as described above for the condensation between compounds (I) and (II), or (I') and (III).
- the substituted benzaldehydes of formulae (II) and (III) are known compounds or can be prepared from readily available starting materials by conventional methods.
- the l,4-diacetyl-2,5-piperazinedione used as a starting material in the preparation of compounds of formula (I) may be prepared by treating 2,5-piperazinedione (glycine anhydride) with an acetylating agent.
- the acetylation may be performed using any conventional acetylating agent, for example acetic anhydride under reflux or, alternatively, acetic anhydride at a temperature below reflux in the presence of 4-dimethylaminopyridine.
- Compounds of formula (I) may alternatively be prepared directly from 2,5-piperazinedione (glycine anhydride) by a process which comprises treating the 2,5- piperazinedione with a mixture comprising a compound of formula (III) , sodium acetate and acetic anhydride at an elevated temperature, for example under reflux.
- Compounds of formula (I') may be prepared by analogous processes, replacing compound (III) in each case by a compound of formula (II) .
- Compounds of formula A may also be prepared by a process comprising the microwave irradiation of (i) a mixture comprising a compound of formula (I) as defined above, a compound of formula (II) and potassium fluoride on alumina, or (ii) a mixture comprising a compound of formula (I') a compound of formula (III) and potassium fluoride on alumina, or (iii) a mixture comprising l,4-diacetyl-2,5- piperazinedione, a compound of formula (II) , a compound of formula (III) and potassium fluoride on alumina.
- Compounds of formula (A) may also be obtained directly by a process which comprises condensing together l,4-diacetyl-2,5-piperazinedione, a compound of formula (II) and a compound of formula (III) in the presence of a base in an organic solvent. Suitable bases, solvents and reaction conditions are as described above for the condensation reaction between, for example, compounds (I) and (II) .
- An alternative direct process for the preparation of compounds of formula (A) comprises condensing together 2,5- piperazinedione, a compound of formula (II) and a compound of formula (III) in the presence of sodium acetate and acetic anhydride at elevated temperature, for example under reflux.
- An alternative process for the preparation of compounds of formula (I) comprises treating a compound of formula (V) :
- R 6 to R 10 are as defined above, X is a halogen and R' is a C 1 -C 6 alkyl group, with ammonia followed by acetic anhydride.
- Compounds of formula (I') may be prepared by an analogous process which comprises treating a compound of formula (V )
- R 1 to R j , X and R 1 are as defined above, with ammonia followed by acetic anhydride.
- X in formula (V) or (V) is typically iodine.
- R 1 is, for example, a C,-C 4 alkyl group such as a methyl, ethyl, propyl, i-propyl, butyl, sec-butyl or tert-butyl group.
- Suitable salts include salts with pharmaceutically acceptable, inorganic or organic, bases.
- inorganic bases include ammonia and carbonates, hydroxides and hydrogen carbonates of group I and group II metals such as sodium, potassium, magnesium and calcium.
- organic bases include aliphatic and aromatic amines such as methylamine, triethylamine, benzylamine, dibenzylamine or ⁇ - or ⁇ -phenylethylamine, and heterocyclic bases such as piperidine, 1-methylpiperidine and morpholine.
- esters include branched or unbranched, saturated or unsaturated C 1 -C 6 alkyl esters, for example methyl, ethyl and vinyl esters.
- Preferred compounds of formula A are depicted by means of their subsitution patterns in Table 1 which follows. The compound numbering is adhered to in the rest of the specification. Characterising data for the compounds are set out in Table 2 in Examole 16. TABLE 1
- the diketopiperazines of formula (A) both novel and known and their pharmaceutically acceptable salts and esters (referred to hereinafter as the "present compounds") have utility as inhibitors of PAI. Elevated levels of PAI- 1, by reducing the net endogenous fibrinolytic capacity, can contribute to the pathogenesis of various thrombotic disorders including myocardial infarction, deep vein thrombosis and disseminated intravascular coagulation. The present compounds therefore can act as inhibitors of the tPA/PAI-1 interaction. The present compounds can be used in the treatment of haemostatic disorders.
- a human or animal e.g.
- a mammal can therefore be treated by a method comprising administration of a therapeutically effective amount of a diketopiperazine of formula (A) or a pharmaceutically or veterinarily acceptable salt thereof.
- Tissue plasminogen activator (tPA) is used as a fibrinolytic agent in the treatment of thrombotic disorders. The efficacy of the tPA in this role may be enhanced if it is administered together with a PAI inhibitor.
- a human or animal e.g. a mammal, can therefore be treated by a method comprising the combined administration of a therapeutically effective amount of tPA and a therapeutically effective amount of any one of the present compounds.
- the present invention also provides products containing a diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester thereof and tPA as a combined preparation for simultaneous, separate or sequential use in the treatment of thrombotic disorders, for example where there is inappropriate PAI activity.
- the present compound is formulated for oral or parenteral (intravenous, intramuscular or subcutaneous) administration and the tPA is formulated for intravenous administration.
- one of the present compounds may be administered to a patient together with tPA to enhance the efficacy of the tPA treatment.
- early re-occlusion following treatment of a patient with tPA may be prevented by the post-MI administration of one of the present compounds.
- the compounds of formula (A) have been tested in a PAI functional assay. In this assay, a compound is incubated with PAI-1 prior to addition to the tPA assay system. Inhibition of PAI-1 results in the production of plasmin from plasminogen.
- plasmin cleaves the chromogenic substrate S2251 (Kabi Vitrum) producing pNA (p- nitroaniline) which is detected spectrophoto etrically at 405 nm (K.Nilsson et al, Fibrinolysis (1987) l , 163-168).
- the results of the assay are reported in Example 1 which follows.
- the present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously.
- the present compounds may therefore be given by injection or infusion.
- the dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult humans is 0.001 to 10 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight. Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration.
- the dosage adopted for each route of administration is typically from 0.001 to 10 mg, more typically 0.01 to 5 mg per kg body weight for a compound of the invention and from 5 to 500mg administered intravenously for the tPA.
- a suitable dosage regimen for the tPA is 100 mg given intravenously over 3 hours as follows: 10% of the total dose as an i.v. bolus over 1-2 minutes, 50% of the total dose as an infusion over 1 hour, 40% of the total dose as an infusion over the subsequent 2 hours.
- a diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester thereof is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent.
- the compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form.
- An agent for use as an inhibitor of PAI comprising any one of the present compounds is therefore provided.
- the solid oral forms may contain, together with the active compound, diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulphates.
- diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch
- lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols
- Such preparations may be manufactured in known manners, for example by means of mixing, granulating, tabletting, sugar coating, or film-coating processes.
- Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
- the syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or annitol and/or sorbitol.
- a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose.
- the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
- Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
- sterile water olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
- Some of the present compounds are insoluble in water.
- a compound may be encapsulated within liposomes.
- EXAMPLE 2 I PHARMACEUTICAL COMPOSITION Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention can be manufactured as follows: Composition for 10.000 tablets compound of the invention (250 g) lactose (800 g) corn starch (415 g) talc powder (30 g) magnesium stearate (5 g)
- the compound of the invention, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml) . The resulting paste is used to granulate the powder. The granulate is dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.
- Compound 16 is treated with ammonia and subsequently with acetic anhydride to yield l-acetyl-3- benzylidenepiperazine-2,5-dione (18) .
- Example 5 Preparation of compound 96 l-Acetyl-3-benzylidene-2,5-piperazinedione (one equivalent), prepared according to Reference Example 1, wa ⁇ treated with 5-(4-formylphenoxy)pentanoic acid, methyl ester in the presence of Cs 2 C0 3 (1-1.1 equivalents) in DMF at 80-100 * C for 1-8 hours. The title compound was obtained in 39% yield.
- Example 6 Preparation of Compound 31 l-Acetyl-3-benzylidene-2,5-piperazinedione (one equivalent) , prepared according to Reference Example 1, was treated with 3-acetoxybenzaldehyde (one equivalent) in the presence of triethylamine (1-2 equivalents) in DMF at 130*C for 2-6 hours. The title compound was obtained in 61% yield.
- 3- acetoxybenzaldehyde by the appropriately substituted benzaldehyde, the following compounds were prepared:
- Example 7 Preparation of compound 103 l-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (1 equivalent) , which is compound (9) mentioned in Example 3, was treated with 2-fluorobenzaldehyde (1 equivalent) in the presence of Cs 2 C0 3 (1-1.1 equivalents) in DMF at 80- 100°C for 1-6 hours. The title compound was obtained in 69% yield.
- Example 8 Preparation of compound 28 l-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (1 equivalent), compound (9) in Example 3, was treated with 2-nitrobenzaldehyde (1 equivalent) in triethylamine (1-2 equivalents) and DMF at 130 " C for 2-6 hours. The title compound was obtained in 45% yield. Characterising data are set out in Example 16.
- Example 9 Preparation of Compound 77 l-Acetyl-3-(4-acetamidobenzylidene)-2,5- piperazinedione (1 equivalent) , prepared according to Reference Example 2, was treated with 2,4- difluorobenzaldehyde (1 equivalent) in the presence of Cs 2 C0 3 (1-1.1 equivalents) in DMF at 80-100"C for 1-6 hours. The title compound was obtained in 60% yield. By the same method, but replacing 2,4- difluorobenzaldehyde by the appropriately substituted benzaldehyde, the following compounds were obtained:
- Example 10 Preparation of compound 22 l,4-Diacetyl-2,5-piperazinedione (1 equivalent), prepared by the published procedure mentioned in Example 3, was treated with benzaldehyde (2.1 equivalents) in the presence of triethylamine (2.5 equivalents) in DMF at 130 ⁇ C for 8 hours. The title compound was obtained in 89% yield. Characterising data are set out in Example 16.
- Example 11 Preparation of compound 35 l,4-Diacetyl-2,5-piperazinedione (1 equivalent), prepared by the published procedure mentioned in Example 3, was treated with 3-nitrobenzaldehyde (1 equivalent) in the presence of triethylamine (1 equivalent) in DMF at room temperature for 18-20 hrs. The title compound was obtained in 9% yield together with l-acetyl-3-(3-nitrobenzylidene)- 2,5-piperazinedione (66% yield). Characterising data are set out in Example 16.
- Example 12 Preparation of Compound 86 l-Acetyl-3-(4-dimethylaminobenzylidene)-2,5- piperazinedione (1 equivalent) as described in Reference Example 3 was treated with 4-acetamidobenzaldehyde (1 equivalent) in the presence of Cs 2 C0 3 (1 equivalent) in DMF at 80*C for 2-6 hours. The title compound was obtained in 56% yield. Characterising data are set out in Example 16.
- Compound 98 the hydrochloride salt of compound 102, was prepared by treatment of a solution of compound 102 in THF with 2 molar hydrochloric acid followed by sonication until a clear solution was obtained. The solvent was then removed in vacuo and the residual solution was freeze-dried to give compound 98.
- Compound 99 was prepared by bubbling HCl gas through a solution of the corresponding free base in THF, followed by evaporation to dryness.
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GB929217331A GB9217331D0 (en) | 1992-08-14 | 1992-08-14 | Pharmaceutical compounds |
GB9217331 | 1992-08-14 | ||
PCT/GB1993/001734 WO1994004512A1 (en) | 1992-08-14 | 1993-08-16 | Pharmaceutically active diketopiperazines |
Publications (2)
Publication Number | Publication Date |
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EP0655060A1 true EP0655060A1 (en) | 1995-05-31 |
EP0655060B1 EP0655060B1 (en) | 1998-01-14 |
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Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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EP93918032A Expired - Lifetime EP0655060B1 (en) | 1992-08-14 | 1993-08-16 | Pharmaceutically active diketopiperazines |
EP93918033A Ceased EP0672036A1 (en) | 1992-08-14 | 1993-08-16 | Pharmaceutically active diketopiperazines |
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EP93918033A Ceased EP0672036A1 (en) | 1992-08-14 | 1993-08-16 | Pharmaceutically active diketopiperazines |
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US (1) | US5700804A (en) |
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